• 专利附录
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    • 专利摘要:
    The compounds of the general formula I <IMAGE> (I) and pharmaceutically acceptable acid addition salts and hydrates thereof possess useful immunostimulant properties and can be used in therapy. In the general Formula I A stands for -CH2-CH2-, -CH2-CH2-CH2-, -CH2-CH2-CH2CH2-or -CH=CH-; R4 is hydrogen, C1-4 alkyl or optionally substituted phenyl; r is 0, 1, 2, 3 or 4; R1 stands for hydrogen of C1-5 alkanoyl; R2 represents hydrogen, C1-5 alkanoyl or a group of the general formula (a) <IMAGE> (a) wherein R stands for hydrogen, C1-4 alkyl, C2-4 alkenyl, phenyl or phenyl-C1-3 alkyl and R3 stands for hydrogen. The compounds of the general Formula I can be prepared by reacting a 2-mercapto-4,6-diamino-pyrimidine of the general Formula II <IMAGE> (II) with a dihalo compound of the general Formula III <IMAGE> (III) (wherein Y and Z are halogen).
    公开号:SU1650014A3
    申请号:SU874203951
    申请日:1987-12-30
    公开日:1991-05-15
    发明作者:Божинг Даниель；Кованьи Дьердьи；Береньи Эдит；Мадьяр Карой；Туболи Шандор；Манди Аттила
    申请人:Эгиш Дьедьсердьяр (Инопредприятие)；
    IPC主号:
    专利说明:

    ABOUT)
    cl
    about
     This invention relates to heterocyclic secretions, in particular to. Method for producing condensed pyrimidine derivatives of general formula
    NH
    P
    .
    (South b N lnn2
    where A is the group -CH2-CH2-, -CH2-CH2- -CH2-, -CH2-CH2-CH2-CH2;
    R is hydrogen, lower alkyl, phenyl;
    r is 1,
    their pharmaceutically acceptable acid addition salts or acid addition salts of hydrates.
    The purpose of the invention is to develop a method for the preparation of new pyrimidine derivatives having a higher biological activity.
    The compounds of general formula (I) have valuable immunostimulating properties.
    J
     WITH
    Microbiological immunity means the protection of the body against pathogens (bacteria, viruses, fungi, parasites) or against their toxic substances. The relevant immunity or its development, along with genetic conditions, can also be influenced by the biological effects of the environment. The cells of the immune system work according to the strict principle of the division of labor. While one recognizes foreign substances (antigens), others produce antibodies or mature into reactive immunocytes. Such cells are also found that coordinate or regulate the connections between certain cell corpses. On the basis of the above, it is also possible to characterize immunity in such a way that the body recognizes foreign substances and can give them a targeted immune response through complex, strictly defined effects of cells.
    From the point of view of prevention against infectious diseases, the so-called active immunity, artificially caused by vaccination, is extremely important. At the same time, a tamed (weakened) version of the pathogen of the disease or a killed pathogen or its toxin is introduced into the body.
    Vaccines used in immunoprophylaxis have different immunogenic effects. Thanks to individual vaccines, one can induce immunity for a lifetime, a considerable part of vaccines provides immunity for only a few months.
    Knowledge or practical use of so-called immunomodulating and immunostimulating substances has led to significant progress in correcting the body's immunodeficiency and in increasing the effectiveness of vaccines with weak immunogenic effects.
    | -at
    The latter is of particular importance.
    in the field of veterinary medicine, since the formation of the immunological homogeneity of large populations of animals is a prerequisite for the same genetic conditions for the production of animals. water level
    0 0 5
    0
    Q
    $
    0
    five
    Experiments related to the study of the immunostimulatory effect of individual compounds show that compounds of the general formula (I) affect the cellular defenses of the body and can increase the immunogenic effect of individual herpesvirus vaccines with weak immunogenic effects (for example, vaccines against Aujeszky disease).
    The results related to the immunostimulating action of compounds of general formula (I) and obtained during model experiments in mice or pigs are given in Table. 1 and 2.
    For reactions in vitro of peripheral lymphocytes, the following test method is used.
    Department of lymphocytes.
    Blood samples from Ficoll Paque were isolated from blood-treated anti-coagulation tests for blood. Cell density is established in Khank's solution containing 10% of fetal serum to 10 / ml. From cell suspensions, measure by |, 5 ml in Leighton tubes and. then supplement them with relevant antigens.
    The formation of immunosols (RCF).
    30% solution of red blood cells of Schafen after the corresponding pre-treatment adsorb through the antigen of Boiven. Of the red blood cells treated in this way, 0.1 ml is injected into Leighton tubes. After 16 h, some of the rosette-forming cells are counted in stained preparations under a microscope.
    Cytotoxic reactions (CT).
    The studies were carried out in an allogenic system. The B-suspension of red blood cells of Schafen, which is susceptible with the help of an antigen, is injected with 0.1 ml of a suspension of lymphocytes with a density of 10 ml cells. The values of cytotoxic ability are determined by the pa basis of hemolysis performed after the incubation period (16 h), which is measured on a Speccol device at 540 nm. The size referred to the control drugs, expressed as a percentage.
    As follows from the data table. 1 and 2, the test compounds generally do not affect the blastogenesis of lymphocytes, however they increase the effectiveness
    cellular immune responses, which is expressed in an 8–11% increase in RCF values and a 10–12% increase in CT-values.
    When comparing the effect of compounds of general formula (I) with the action of compound TEI-3096, the following difference is found. While the known compound activates only T-cells of the suppressor, compounds of the general formula (I) increase the activity of T-suppressor lymphocytes and other so-called K-cells, which results in an increase in the cytotoxic ability of the cellular immune system.
    The toxicity of the compounds of formula (I), in particular the compounds of example 1, LD gQ on one individual of mice in CMC suspensions of 2000 mg / kg.
    Example 1. 7-amino-5-imino-2,3-dihydro-5H-thiazolo- (3,2-a) -pyrimidine-hydrobromide.
    A mixture of 14.2 g (0.1 mol) of 2-mercapto-4,6-diaminopyrimidine, 21.6 g (0.115 mol) of ethylene dibromide, 200 ml of dimethylformamide and 13.8 g (0.1 mol) of potassium carbonate are stirred at 70 ° C for 5 hours. The reaction mixture is cooled, precipitated, the product is filtered, washed with water and dried. 23.6 g of the expected compound are obtained, yield 95%, m.p. above 300 ° C. Calculated,% :. C, 28.93; H 3.64; N 22.49; S 12.87; Br 32.07
    , BrN4S 249,136
    Found,%: C 28.88; H 3.68; N 22.66; S 12.70; Br 32.08
    EXAMPLE 2. 8-Amino-b-imino-3,4-dihydro-2H, 6H-pyrimido- (2,2-b) (1,3) -thiazine -hydrobromide.
    Method A.
    14.9 g (0.1 mol) of 2-mercapto-4,6-diaminopyrimidine and 23.9 g (0.115 mol of 1,3-dibromo-propane are converted as in Example 2. After treating the reaction mixture, 23.7 g of the title compound are obtained. yield 90%, mp above 300 ° C.
    Calculated,%: C, 31.95; H 4.21; N 21.29; S 12.18; Br 30.36
    C7HflBrN4S 263, l63
    Found,%: C 32.38; H 4.24; N 21.10; S 12.04; Br 30.76
    Method B.
    14.2 g (0.1 mol) of 2-mercapto-4, b-diaminopyrimidine and 15.8 g (0.1 mol) of 1,3-chloro-bromo-propane are converted,
    analogously to example 2. After treatment of the reaction mixture, 17.1 g of the title compound are obtained, yield 65%, mp. above 300 ° C.
    Calculated,%: C, 31.95; H 4.21; N 21.29; S 12.18; Br 30.36 C7H11Bi-N4S 263.163 Found: C 33.18; H 4.52; 0 N 21.28; S 12,10; Vg 30.85
    EXAMPLE 3: 7-Amino-2-phenyl-5-imino-2,3-dihydro-5H-thiazolo- (3,2-a) - pyrimidine-hydrobromide.
    A mixture of 14.2 g (0.1 mol) of 2-mercap-5 to-4,6-diaminopirnmidine, 30.4 g (0.115 mol) of (1,2-dibromoethyl) benzene, 200 ml of dimethylformamide and 13.8 g (0.1 mol) potassium carbonate is stirred at 45 ° C for 6 hours, 0 The reaction mixture is cooled, the precipitated product is filtered, washed with water and dried. 26.0 g of the title compound are obtained, yield 80%, m.p. above 300 ° C.
    5 Calculated,%: C, 44.32; H 4.03; N 17.23; S 9.85; Br 24.57 C, 2.Hl3BrN4., 235 Found: C 44.52; H 4.04; N 17.10; S 9.81; Br 25.05 0 Example4. 8-amino-6-imino73-methyl-2H, 6 H-pyrimido- (2,1-b) (1,3) - thiazine-hydrobromide.
    14.2 g (0.1 mol) of 2-mercapto 4,6-diaminopyrimidine and 19.7 g (0.115 mol) of 5 2-methyl-1,3-chloro-bromo-propane are transformed as in Example 2. After treatment, the reaction mixture is obtained 18 g of the title compound, 65% yield, mp. above 300 ° C. 0 Calculated,%: C 34.67; H 4.73; N 20.21; S 11.57; Br 28.83 CgH BrN4S 277, l9 Found:% 34.68; H 4.80; N 19.96; S 11.40; Br 29.39 5 Example5. 7-amino-5-imino-3 "(or 2) -methyl-2H, 5H-thiazolo- (3,2-a) - pyrimidine-hydrobromide.
    14.2 g (0.1 mol) of 2-mercapto-4, diaminopyrimidine and 23.2 g (0.115 mol 3 of 1,2-dibromo-propane are converted in analogy to example 2. After treating the reaction mixture, 15.8 g of p are obtained, e of the left compound, yield 60%, mp above 300 ° C.
    5 Calculated,%: C, 31.95; H 4.21; N 21.29; S 12.18; Br 30.36 CTHMBrN4S 263, l63 Found 9%: C 32.50; H 4.47; N 21.24; S 11.97; Br 30.79
    EXAMPLE 6. 7-Amshu-5-imino-2,3-dihydro-5H-thiazolo- (3,2-a) -iri midin-gdprocarbonate-dihydrate.
    To a solution of 224 g of sodium bicarbonate and 2500 ml of water, 24.9 g (0.1 mol) of 7-amino-5-imino 2,3-dihydro-5H thiazolo (3,2-a) -pyrimidine hydrobromide. The reaction mixture is stirred at room temperature for 8 hours, then filtered. The product is washed with water and dried. 17.2 g of the expected compound are obtained, yield 75%, mp 146-148 ° C.
    Calculated,%: With ST, 70; H 4.94; N 21.12; S 12.09;
    C7H ,, N405s265,266
    Found,% s C 32,68; H 4.70; N 20.09; S 12,18
    Example. b-Amino-b-imino-3,4-dihydro-2H, 6H-pipyido- (2,1-b) (1,3) -thiazine-bicarbonate-dihydrate
    The indicated compound is obtained from 26.3 g (0.1 mol) of 8-amino-6-imino-3,4-dihydro-2H, 6H-pyrimido- (2,1-b (, 3) diazine hydrobromide, analogously to the example 8. Yield 17 g (70%), mp: 1% 198 ° C.
    Calculated,%: C 34.40; H 5.41; N 20.06; S 11.48
    C8H, 5H405-279,293.
    Found,%: C 35.65; H 5.52; N 19.57; S 11.32
    Example 8. 7-Amino-5-imino-2,3-DIHIDRO-5H-giazolo- (3,2-a) -pyrimidine.
    A mixture of 5.3 g (0.02 mol) of 7-amino 5-imino 2,3-dihydro-5H-thiazolo (3,2-a) pyrimidn-bicarbonate-dihydrate and 30 ml of acetic acid is stirred for 6 h. The solution is evaporated, the remaining crystals are absorbed in ethanol, filtered and dried. 3.6 g of the expected compound are obtained, yield 59.5%, m.p. 158-160 ° C.
    Calculated,%: C 43.70; H 6.00;
    CHH, 8N404 320,351
    Found,%: C 43.68; II 5.97
    Example 9. 9 Amino 7-imino-2 3,4,5-tetrahydro 7H-thiazepino- (1,3-a (3,2-a) -pyrimidine-hydrobromide,
    A mixture of 14.2 g (0.1 mol) of 2-mercapto-4,6-diamino-pyrimidine, 24.8 g (0S15 mol) of 1,4-dibromo-butane, 200 ml of dimethylformamide and 13.8 g ( O, 1 mol) of potassium carbonate heating
    11 h at 80 ° C, the precipitated inorganic salt is filtered, the filtrate after clarification is concentrated and cooled to. The precipitated product is filtered, washed with isopropanol and dried. 23.3 g of the title compound are obtained, yield 84%. If necessary, the product can be recrystallized from a 10-fold amount of 50% aqueous ethanol. M.p. 283–284 bs.
    Calculated,%: C 34.66; H 4.73; N 20.21; S 11.57; Br 28.83
    CgH0BrN4S 277.19
    Found,%: C 34.65; H 4.76; N 19.58; S 11.35; Br 28.19
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    The method of obtaining condensed
    pyrimidine derivatives of general formula I
    (RVSTTNH "
    where A is -CH2-CH2-, -CH2-CH2-CH2-, CH2-CH2-CH2-C1 2-;
    V. - hydrogen, lower alkyl, phenyl; ,
    , their pharmaceutically acceptable acid addition salts or acid addition salts of hydrates, as a result of the fact that 2-mercapto-4,6-diamspyrimidine of general formula II
    Mno
    40
    N-
    NH
    . are reacted with a dihalopyridine derivative of general formula III
    J-A-Z,
    Where. And Z - Halogen,
    R r have the indicated values, in the presence of an acid binding agent in an inert organic solvent at a temperature of 45 ° C to the boiling point of the reaction mixture, liberating or in the form of pharmaceutically acceptable acid addition salts or hydrate acid addition salts.
    Model experience with mice
    Note: The numerator indicates the samples collected for the 1st or 3rd or 4th week of the animals treated with the combination of the compound and the vaccine, expressed as a percentage. The denominator indicates the corresponding values when the animals are treated only with a vaccine.
    RCF - formation of immune sockets. CT - cytotoxic reactions.
    Model experience with pigs
    Table 1
    table 2
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    同族专利:
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    AU8314487A|1988-06-30|
    FI875766A0|1987-12-30|
    DK692587D0|1987-12-30|
    NL8703148A|1988-07-18|
    CN87105992A|1988-08-10|
    YU46483B|1993-10-20|
    FI86637C|1992-09-25|
    CH676599A5|1991-02-15|
    FR2609033A1|1988-07-01|
    CA1324788C|1993-11-30|
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    CN1024277C|1994-04-20|
    PL149618B1|1990-03-31|
    SE8705196L|1988-07-01|
    SE8705196D0|1987-12-30|
    FI875766A|1988-07-01|
    KR940002669B1|1994-03-28|
    IL84988D0|1988-06-30|
    US4921854A|1990-05-01|
    AU597770B2|1990-06-07|
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    KR880007545A|1988-08-27|
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    FR2609033B1|1994-09-09|
    BE1003067A5|1991-11-12|
    PL269811A1|1988-09-15|
    引用文献:
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    DE102004035808A1|2004-07-21|2006-03-16|Kasch, Helmut, Dr.|Ammonium salts and ammonium salt-Mineralaltschlatrate as a transport and Wirkform for pharmaceutical-medical and as a phase transfer agent for chemical applications|
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    PE20210948A1|2018-08-03|2021-05-24|Cadent Therapeutics Inc|HETEROAROMATIC NMDA RECEIVER MODULATORS AND USES OF THEM|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    HU865514A|HU196763B|1986-12-30|1986-12-30|Process for production of piramidine-derivatives|
    HU551286A|HU197913B|1986-12-30|1986-12-30|Process for producing thiazolo-, thiazino- and thiazepinopyrimidine derivatives|
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